This invention relates to novel iodoaromatic compounds and their preparation and to x-ray contrast media based thereon.
For examination by roentgenography, for example, of urine-excreting organs and vessels by angiography, compatible salts of 2,4,6-triiodobenzoic acids have been developed as contrast media. These compounds, however, are not tolerated at high dosages without side effects to the human or animal patient, although toxicity is frequently minor. Adequate visualization of the vascular system, the urinary tract, and the cerebrospinal cavities and other systems requires use of high dosages of contrast media, or of highly concentrated solutions. The physico-chemical properties of the contrast media and solutions thereof become important owing to pharmacological effects, including pain, blood pressure drop, and vessel damage attributed to the contrast media.
Dimeric hexaiodated dicarboxylic acids have better neural compatibility and lead to less vasodilation in angiography than monomeric triiodated benzoic acids. Owing to somewhat lower osmotic pressure, for example, dimeric iocarminic acid dimeglumine salt has a relatively high resulting concentration in the urine.
The U.S. Pat. No. 3,701,771 discloses nonionic x-ray contrast media containing, for example, metrizamide, 2-(3-acetamido-5-N-methylacetamido-2,4,6-triiodobenzamido)-2-deoxy-D-gluco se. These media are inferior to those of the invention, as will be demonstrated with reference to the tables below.
3-Acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids are known from U.S. Pat. No. 3,145,197. Several amino acid derivatives of 3-acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids have likewise been described, e.g., 5-acetamido-2,4,6-triiodoisophthaloyl diglycine in U.S. Pat. No. 3,102,880 and N-[3-N-(alkyl-acylamino)-5-alkylcarbamoyl-2,4,6-triiodobenzoyl]-amino acids in Helv. Chim. Acta 54 (8): 2551-2559 (1971). Although these compounds have a low toxicity, they have several undesirable side effects. For example, they do not meet the high requirements to be fulfilled by a medium for myelography, e.g., see Ugeskrift for laeger 134 (18): 936 (1972) and Advances in X-Ray Technology 115: 683-684 (1971).
Other teachings on highly iodinated aromatic compounds are those of Erich Klieger et al., U.S. Pat. No. 3,953,501; Heinz Gries et al., U.S. Pat. No. 4,001,298; Heinz Gries, U.S. Pat. No. 3,883,578; and Erich Klieger et al., Ser. No. 555,043, filed Mar. 3, 1975, now U.S. Pat. No. 4,032,567, the disclosures of which are herein incorporated by reference.